Team Uncovers Drug Resistance Mechanism that Could Impact Development of Two Antibiotic Drugs

By Eric Sauter

The use of antibiotics is often considered among the most important advances in the treatment of human disease. Unfortunately, though, bacteria are finding ways to make a comeback. According to the Centers for Disease Control, more than two million people come down with antibiotic-resistant infections annually, and at least 23,000 die because their treatment can’t stop the infection. In addition, the pipeline for new antibiotics has grown dangerously thin.

Now, a new study by scientists from the Florida campus of The Scripps Research Institute (TSRI) has uncovered a mechanism of drug resistance. This knowledge could have a major impact on the development of a pair of highly potent new antibiotic drug candidates.

“Now, because we know the resistance mechanism, we can design elements to minimize the emergence of resistance as these promising new drug candidates are developed,” said Ben Shen, a TSRI professor who led the study, which was published February 20, 2014 online ahead of print by the Cell Press journal Chemistry & Biology.

Bacteria Versus Bacteria

The study centers around a kind of bacteria known as Streptomycesplatensis, which protects itself from other bacteria by secreting anti-bacterial substances. Interestingly, Streptomycesplatensis belongs to a large family of antibiotic-producing bacteria that accounts for more than two-thirds of naturally occurring clinically useful antibiotics.

The antibiotic compounds secreted by Streptomycesplatensis, which are called platensimycin and platencin and were discovered only recently, work by interfering with fatty acid synthesis. Fatty acid synthesis is essential for the production of bacterial cell walls and, consequently, the bacteria’s existence. Platencin, although structurally similar to platensimycin, inhibits two separate enzymes in fatty acid synthesis instead of one.

The question remained, though, of why these compounds killed other bacteria, but not the producing bacteria Streptomycesplatensis.

The Path to Resistance

The scientists set out to solve the mystery.

“Knowing how these bacteria protect themselves, what the mechanisms of self-resistance of the bacteria are, is important because they could transfer that resistance to other bacteria,” said Tingting Huang, a research associate in the Shen laboratory who was first author of the study with Ryan M. Peterson of the University of Wisconsin, Madison.

Using genetic and bioinformatic techniques, the team identified two complementary mechanisms in the bacteria that confer resistance to platensimycin and platencin. In essence, the study found a pair of genes in Streptomycesplatensis exploits a pathway to radically simplify fatty acid biosynthesis while bestowing an insensitivity to these particular antibiotics.

“Understanding how these elements work is a big leap forward,” added Jeffrey D. Rudolf, a research associate in the Shen lab who worked on the study. “Now these bacteria have shown us how other bacteria might use this resistance mechanism to bypass fatty acid biosynthesis inhibition.”

In addition to Shen, Huang, Peterson and Rudolf, the study, “Mechanisms of Self-Resistance in the Platensimycin and Platencin Producing Streptomyces Platensis MA7327 and MA7339 Strains,” was authored by Michael J. Smanski of the University of Wisconsin, Madison. For more information, see http://www.cell.com/chemistry-biology/abstract/S1074-5521(14)00028-3

The study was supported by the National Institutes of Health (Grant Numbers AI079070 and GM08505).

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Authors of the new study, which uncovered a mechanism of drug resistance, include (left to right) Professor Ben Shen, Research Associate Jeffrey Rudolf and Research Associate Tingting Huang.